Asiatic acid (2α,3β,23-trihydroxy-ursa-12-en-28-oic acid), was first extracted from Centella asiatica by Bontems et al. The pharmacologic effects of asiatic acid are quite wide. It can be used to treat burn, chronic ulcers, or skin deformity associated with tuberculosis or leprosy. It also owns a certain curative effect on cardiovascular disease, hepatotoxicity and so on. Moreover, some study discloses that asiatic acid has an effect on anti-depression, anti-fibrosis, antibiosis, antineoplastic, anti-oxidation, etc.
Although there exists four hydrophilic groups (3 hydroxyl groups and 1 carboxyl group) in the molecular structure, the wettability of asiatic acid is relatively poor, and it is practically insoluble in water. Physicochemical properties require a particular process method and excipient in the formulation of preparations for topic use, especially hydrophilic use. In addition, it is known that the cutaneous absorption primarily proceeds transepidermally (intra- and trans-cellular) and it is mainly controlled by the effect of effective components on the cuticle that mainly consists of keratin and water. Therefore, besides the formulation problem, a proper bioavailability of asiatic acid at an epidermis level remains to be realized.
Salts of asiatic acid are protonated salts formed by asiatic acid and pharmaceutically acceptable alkali. The water solubility of salts of asiatic acid is better than that of asiatic acid, which makes the development of salts of asiatic acid quite significant.
The salts of asiatic acid with hemi-succinate, salts of hemi-succinate, as well as with alkylaminoalkanols and dialkylaminoalkanols have been reported currently by U.S. Pat. No. 3,366,669. CN 1238330C disclosed salts of asiatic acid with ethylenediamine, ethanolamine, diethanolamine, lysine, benzyltrimethylammonium hydroxide, and tetramethylammonium hydroxide etc. WO 2009/089365 disclosed the ammonium salt, sodium salt, potassium salt, sodium carbonate salt, sodium phosphate salt, amino triacetate salt, and trometamol salt of asiatic acid.
The compounds aforementioned all can be used to prepare the aqueous solution for topic pharmaceutical use.
The solubility of the known free acid of asiatic acid, trometamol salt of asiatic acid reported in WO 2009/089365 and other salts of asiatic acid is all unsatisfactory. How to prepare a kind of trometamol salt of asiatic acid with much higher solubility as well as good bioavailability is always the research issue for the scientists at present.